Project Summary/Abstract Inflammation associated with pancreatitis initiates accumulation of leukocytes within the pancreas. Chief among these cells are macrophages, neutrophils, and T cells. Although studies have identified important roles for each of these cell types in pancreatitis, most of the focus has been on macrophages, as they are thought to be potent drivers of inflammatory cytokine production. Despite this, targeting macrophage-produced cytokines has not seen much success therapeutically. This, along with the fact that pancreatitis is a well described risk factor for pancreatic cancer, illustrates the need for establishing better ways to target the cell types driving disease progression. Although macrophages are an attractive therapeutic target in both pancreatitis and pancreatic cancer, study thus far has primarily focused on those derived from infiltrating monocytes. Recent lineage-tracing studies have shown that macrophages within tissues originate not only from monocytes, but also from embryonic progenitors during fetal development. Further, it has been shown that in some models of pathogenesis, including pancreatic cancer, embryonic-derived macrophages adopt unique functions from those derived from monocytes. Study of pancreatic cancer also revealed that embryonic macrophages may uniquely promote tumor progression and changes in fibrosis. However, it is not fully understood what mechanisms drive macrophages of different origin to react differently, and how embryonic-derived macrophages might impact tumor progression differently than those derived from monocytes. I hypothesize that macrophages of different origin adopt functionally distinct roles in both pancreatitis and pancreatitis-associated pre-malignant progression. Preliminarily, I have shown that both embryonic and monocyte-derived macrophages accumulate in the pancreas during pancreatitis. Additional lineage-tracing mouse models will be used here to strengthen this argument and allow me to investigate changes in activation of these populations between steady-state and inflammation. Reducing monocyte-derived macrophages by genetic deletion of the CCR2 gene, involved in monocyte trafficking, is not sufficient to restrain total macrophage numbers in the pancreas during pancreatitis, and these mice show no difference in disease progression. Targeting the embryonic macrophage subset may further help us understand the functional role of these cells and determine their therapeutic efficacy. These aims will not only help expand our knowledge of macrophage biology, but also focus on my long-standing interests in immunology and human disease. The training received through this proposal will also build upon my technical skills in immunology and study of cancer biology. These invaluable skills will allow me to further push towards my career goals of improving cancer immunotherapies and impact of immune modulation on inflammatory disorders.